Altered Resting-State Connectivity within Executive Networks after Aneurysmal Subarachnoid Hemorrhage

2020

Neurotherapeutics

Cortical spreading depolarizations (SD) are strongly associated with worse tissue injury and clinical outcomes in the setting of aneurysmal subarachnoid hemorrhage (SAH). Animal studies have suggested a causal relationship, and new therapies to target SDs are starting to be tested in clinical studies. A recent set of single-center randomized trials assessed the effect of the phosphodiesterase inhibitor cilostazol in patients with SAH. Cilostazol led to improved functional outcomes and SD-related metrics in treated patients through a putative mechanism of improved cerebral blood flow. Another promising therapeutic approach includes attempts to block SDs with, for example, the NMDA receptor antagonist ketamine. SDs have emerged not only as a therapeutic target but also as a potentially useful biomarker for brain injury following SAH. Additional clinical and preclinical experimental work is greatly needed to assess the generalizability of existing therapeutic trials and to better delineate the relationship between SDs, SAH, and functional outcome.

Section: Mechanistic Studiesmentioning

confidence: 99%

Spreading Depolarizations and Subarachnoid Hemorrhage

Sugimoto

2020

Neurotherapeutics

“…4 Recent studies using functional neuroimaging have found an association between these persistent cognitive deficits and alterations in neuronal networks after SAH using fMRI or magnetoencephalography. 5–7 In one study, altered measures of resting state functional connectivity (RSFC) were associated with worse performance on the Montreal Cognitive Assessment, a test of mild cognitive impairment. 7 Another study found that altered RSFC was associated with decreased executive dysfunction and worse quality of life as measured by a battery of standard cognitive tests.…”

Section: Introductionmentioning

confidence: 99%

“…7 Another study found that altered RSFC was associated with decreased executive dysfunction and worse quality of life as measured by a battery of standard cognitive tests. 6 However, a causal relationship between altered functional connectivity and cognitive deficits is not yet established, in part because of a lack of experimental models.…”

Section: Introductionmentioning

confidence: 99%

Subarachnoid hemorrhage leads to early and persistent functional connectivity and behavioral changes in mice

J Cereb Blood Flow Metab

Oka

Jin

et al. 2020

Aneurysmal subarachnoid hemorrhage (SAH) leads to significant long-term cognitive deficits, which can be associated with alterations in resting state functional connectivity (RSFC). However, modalities such as fMRI—which is commonly used to assess RSFC in humans—have practical limitations in small animals. Therefore, we used non-invasive optical intrinsic signal imaging to determine the effect of SAH on RSFC in mice up to three months after prechiasmatic blood injection. We assessed Morris water maze (MWM), open field test (OFT), Y-maze, and rotarod performance from approximately two weeks to three months after SAH. Compared to sham, we found that SAH reduced motor, retrosplenial, and visual seed-based connectivity indices. These deficits persisted in retrosplenial and visual cortex seeds at three months. Seed-to-seed analysis confirmed early attenuation of correlation coefficients in SAH mice, which persisted in predominantly posterior network connections at later time points. Seed-independent global and interhemispheric indices of connectivity revealed decreased correlations following SAH for at least one month. SAH led to MWM hidden platform and OFT deficits at two weeks, and Y-maze deficits for at least three months, without altering rotarod performance. In conclusion, experimental SAH leads to early and persistent alterations both in hemodynamically derived measures of RSFC and in cognitive performance.

“…Many survivors of SAH suffer from persistent cognitive problems [3] with the majority not being able to return to work or resume their previous activities [4]. Recent studies using functional neuroimaging have found an association between these persistent cognitive deficits and alterations in neuronal networks after SAH using fMRI or magnetoencephalography [5][6][7]. In one study, altered measures of resting state functional connectivity (RSFC) were associated with worse performance on the Montreal Cognitive Assessment, a test of mild cognitive impairment [7].…”

Section: Introductionmentioning

confidence: 99%

“…In one study, altered measures of resting state functional connectivity (RSFC) were associated with worse performance on the Montreal Cognitive Assessment, a test of mild cognitive impairment [7]. Another study found that altered RSFC was associated with decreased executive dysfunction and worse quality of life as measured by a battery of standard cognitive tests [6]. However, a causal relationship between altered functional connectivity and cognitive deficits is not yet established, in part because of a lack of experimental models.…”

Section: Introductionmentioning

confidence: 99%

Subarachnoid hemorrhage leads to early and persistent functional connectivity and behavioral changes in mice

Oka

Jin

et al. 2019

Preprint

Aneurysmal subarachnoid hemorrhage (SAH) leads to significant long-term cognitive deficits. Studies in survivors of SAH show an association between persistent cognitive deficits and alterations in resting state functional connectivity (RSFC). However, modalities commonly used to assess RSFC in humans, such as fMRI, have practical limitations in small animals. Therefore, we used non-invasive functional optical intrinsic signal imaging to determine the effect of SAH on measures of RSFC in mice at early (day 4), intermediate (1 month), and late (3 months) time points after prechiasmatic arterial blood injection. We assessed Morris water maze, open field test, Y-maze, and rotarod performance from approximately 2 weeks to 3 months after SAH induction. We found qualitative and quantitative differences in seed-based connectivity maps between sham and SAH mice. SAH reduced motor, retrosplenial and visual seed-based connectivity indices, which persisted in retrosplenial and visual cortex seeds at 3 months. Seed-toseed connectivity analysis confirmed attenuation of correlation coefficients in SAH mice, which persisted in predominantly posterior network connections at later time points. Seedindependent global and interhemispheric indices of connectivity revealed decreased correlations following SAH for at least 1 month. SAH led to Morris water maze hidden platform and open field deficits at 2 weeks, and Y-maze deficits for at least 3 months, without altering rotarod performance. In conclusion, experimental SAH leads to early and persistent alterations both in hemodynamically-derived measures of RSFC and in cognitive performance.